PTEN c.70G>A, p.Asp24Asn
NM_000314.8:c.70G>A
COSMIC ID: COSM5079
Likely Pathogenic
Using classification after pre-processing (Likely Pathogenic) due to LLM failure: LLM interpretation failed: API Error - Status: 429, Message: Error code: 429 - {'error': {'message': 'You exceeded your current quota, please check your plan and billing details. For more information on this error, read the docs: https://platform.openai.com/docs/guides/error-codes/api-errors.', 'type': 'insufficient_quota', 'param': None, 'code': 'insufficient_quota'}}
ACMG/AMP Criteria Applied
BP4
PM2
PP5
PS3
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.70G>A
Protein Change
D24N
Location
Exon 1
(Exon 1 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Missense Variant
Related Variants
No evidence of other pathogenic variants at position 24 in gene PTEN
Alternate Identifiers
COSM5079
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.70G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The p.D24N pathogenic mutation (also known as c.70G>A), located in coding exon 1 of the PTEN gene, results from a G to A substitution at nucleotide position 70. The aspartic acid at codon 24 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in individuals with features consistent with PTEN hamartoma tumor syndrome in at least one individual, it was determined to be de novo (external communication). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955).This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 24 of the PTEN protein (p.Asp24Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 185200). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 17213812). This variant disrupts the p.Asp24 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24778394, 29706633; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 24 in gene PTEN
Functional Summary
Error in OpenAI Consolidation. OncoKB: PTEND24NPTEND24NSomaticNCBI Gene:5728|Show additional gene information Variant OverviewPTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.The PTEN D24N mutation is likely oncogenic.Hide mutation effect description The PTEN D24N mutation is located in the phosphatase domain of the protein. This mutation has been found in endometrial cancer (PMID: 17213812). Expression of this mutation in human embryonic kidney cell line demonstrated that it is inactivating as measured by increased protein mislocalization despite no change in protein phosphatase activity compared to wildtype (PMID: 17213812).
JAX-CKB: PTEN D24N lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). D24N retains phosphatase activity, but has aberrant nuclear localization and fails to inhibit Akt phosphorylation, cell proliferation, and transformation in cell culture (PMID: 17213812) and therefore, confers a loss of function to the Pten protein.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.26polyphen_prediction: benign
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
BP4
BP4 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)
PM2
PM2 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)
PP5
PP5 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)
PS3
PS3 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)